Envelope glycoprotein determinants of pathogenic, macrophage-tropic HIV-1 and their role in HIV-1 disease progression

点击翻译按钮获取中文摘要

Human immunodeficiency virus type 1 (HIV-1) causes AIDS and, to date, has infected 20 thousand people in Australia and 40 million worldwide. In addition to T-cells of the immune system, HIV-1 can also infect cells of the monocyte-macrophage lineage found in blood, brain, lymph node, lungs, bone marrow, skin and brain. HIV-1 strains that can infect these cells are called macrophage-tropic (M-tropic) strains. Infected macrophages are a major source of new HIV-1 produced in the body, and they complicate therapy by the current drugs used to treat HIV-1 infection because infection is often latent (or dormant) and, unlike T-cells, they are long lived and may continue to produce new virus for the duration of their normal life span. HIV-1 virus from patients with advanced disease (i.e. AIDS) can infect macrophages better than virus from patients at early stages of disease (i.e. just after infection, or during the asymptomatic or healthy period). Therefore, the increased ability of HIV-1 to infect macrophages, i.e., enhanced M-tropism, is an important factor contributing to the development of AIDS in people with HIV-1 infection. However, what causes HIV-1 to increase it's ability to infect macrophages and cause AIDS is unknown. This proposal aims to identify features of HIV-1 that are important for enhanced M-tropism and HIV-1 disease progression. We expect to find that the virus gradually changes during the course of infection to forms that can bind to receptor molecules on the cell more tightly, and to forms that need fewer receptors on the cell surface for infection. We believe that these forms of HIV-1 virus are now better able to infect macrophages, which naturally only have small amounts of receptors on their surface, and also can infect and kill T-cells better, leading to AIDS. This study will contribute to a greater understanding of how HIV-1 causes AIDS, which is necessary for the development of new drugs to treat HIV-1 infection.